In many diseases, for example, rheumatism, arthritis, osteoporosis, inflammatory colitis, immune deficiency syndrome, ichorrhemia, hepatitis, nephritis, ischemic diseases, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease, and leukemia, an increased production of interleukin-1β, which is an inflammatory cytokine, is observed. This interleukin-1β serves to induce synthesis of an enzyme which is considered to take part in inflammation—like collagenase and PLA2- and, when intra-articularly injected to animals, causes multiarticular damage highly resembling rheumatoid arthritis. In a healthy body, on the other hand, the activity of interleukin-1β is controlled by interleukin-1 receptor, soluble interleukin-1 receptor and interleukin-1 receptor antagonist.
From research conducted using recombinant bioactivity-inhibiting substances, anti-interleukin-1β antibodies and anti-receptor antibodies against various disease models and also from research performed using knockout mice, interleukin-1β has been found to play an important role in the body, leading to an increasing potential of substances having interleukin-1β inhibitory activity as therapeutics for such diseases.
For example, immunosuppressors and steroids, which are used for the treatment of rheumatism among these many diseases, have been reported to inhibit production of interleukin-1β. Among compounds currently under development, KE298, a benzoylpropionic acid derivative [The Japanese Society of Inflammation (11th), 1990], for example, has been reported to also exhibit inhibitory activity against interleukin-1β production although it is an immunoregulator. Inhibitory activity against interleukin-1β production is also observed in a group of compounds which are called “COX-2 selective inhibitors”, for example, nimesulide as a phenoxysulfonanilide derivative (DE Publication No. 2333643), T-614 as a phenoxybenzopyran derivative (U.S. Pat. No. 4,954,518), and tenidap (oxyindole derivative) as a dual inhibitor (COX-1/5-LO).
However, interleukin-1β production inhibitory activity is not the primary action or effect of any of these compounds so that the inhibitory activity against interleukin-1β production is less than the primary action thereof.
More recently, increased synthetic research has been conducted emphasizing inhibitory activity against interleukin-1β production. Production inhibitors can be classified into a group of compounds which inhibit the transfer process and an inflammatory signal to a cell nucleus, the transcription or translation stage, and another group of compounds which inhibit the enzyme ICE that functions in the processing of a precursor of interleukin-1β. Known examples of compounds presumed to have the former action include SB203580 [JP-A-1995-503017], FR167653 (Eur. J. Pharm., 327, 169–175, 1997), E-5090 (EP Patent Publication No. 376288), CGP47969A (Gastroenterology, 109, 812–818, 1995), hydroxyindole derivatives (Eur. J. Med. Chem. 31, 187–198, 1996), and triarylpyrrole derivatives (WO 9705878), while known examples of compounds presumed to have the latter action include VE-13,045 which is a peptide compound (Cytokine, 8(5), 377–386, 1996).
None of these compounds, however, exhibit sufficient inhibitory activity against interleukin-1β production.
On the other hand, it is known that 5,6-diphenyl-pyridazine derivatives exhibit analgesic and anti-inflammatory action (Eur. J. Med. Chem., 14, 53–60, 1979). Further, 6-phenylpyridazinones have been reported to be useful as cardiotovics (U.S. Pat. No. 4,404,203). Nothing has been reported, however, with respect to inhibitory activity of these pyridazine compounds against interleukin-1β production.
The present inventors previously reported in WO 99/44995 that high inhibitory activity against interleukin-1β production was observed on phenylpyridazine derivatives. Recently, certain phenylpyridazine derivatives having inhibitory activity against interleukin-1β production have been reported (JP 7-69894 A, WO 98/41511, WO 99/10331, WO 99/10332, WO99/25697, WO00/50408). These reported compounds, however, are different in chemical structure from the compounds of the present invention.